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T h e new england journal o f

Review article

Medical Progress in Solid- Transplant Recipients Jay A. Fishman, M.D.

ncreasingly potent immunosuppressive agents have dramatically From the Transplant Infectious Disease reduced the incidence of rejection of transplanted organs while increasing pa- and Compromised Host Program, Massa- 1,2 chusetts General , and Harvard tients’ susceptibility to opportunistic and . At the same time, , Boston. Address reprint I requests to Dr. Fishman at the Transplant patterns of opportunistic infections after transplantation have been altered by routine antimicrobial prophylaxis for Pneumocystis carinii (also called P. jirovecii) and cytomega- Infectious Disease and Compromised Host Program, Massachusetts General lovirus. These patterns have also been altered by the emergence of new clinical syn- Hospital, 55 Fruit St., GRJ 504, Boston, dromes (e.g., polyomavirus type BK nephropathy) and by infections due to organisms MA 02114, or at [email protected]. with antimicrobial resistance. New quantitative molecular and -based micro- N Engl J Med 2007;357:2601-14. biologic assays detect previously unrecognized transplantation-associated pathogens Copyright © 2007 Massachusetts Medical Society. such as lymphocytic choriomeningitis . These assays are used in the manage- ment of common infections such as those due to and Epstein–Barr virus (EBV). In this article, I review general concepts in the management of trans- plantation-associated infections and discuss recent advances and challenges.

GENERAL CONCEPTS

It is more difficult to recognize infection in transplant recipients than it is in persons with normal immune function, since signs and symptoms of infection are often di- minished. In addition, noninfectious causes of fever, such as allograft rejection, may develop in transplant recipients. Antimicrobial frequently has toxic effects that may involve interactions with immunosuppressive agents. The spectrum of po- tential pathogens is broad, and infection often progresses rapidly. Early and specific microbiologic diagnosis is essential for guiding treatment and minimizing nones- sential drug therapy. Invasive diagnostic procedures are often required for accurate and timely diagnosis.

RISK OF INFECTION

The risk of infection after transplantation changes over time, particularly with mod- ifications in . Unfortunately, no assays accurately measure a pa- tient’s risk of infection. Currently, therefore, the clinician assesses a recipient’s risk of infection while considering the risk of allograft rejection, the intensity of immuno- suppression, and other factors that may contribute to his or her susceptibility to in- fection. Prophylactic strategies are based on the patient’s known or likely exposures to infection according to the results of serologic testing and epidemiologic history. The risk of infection in the transplant recipient is a continuous function of the in- terplay between these factors.

Epidemiologic Exposures Epidemiologic exposures can be divided into four overlapping categories: donor-derived infections, recipient-derived infections, nosocomial infections, and community infec- tions.

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Donor-Derived Infections and Screening Transplanted organs facilitate the of A infections from organ donors. Mandatory report- ing of transplantation-associated infections has increased awareness of this problem. Most often, these infections (e.g., cytomegalovirus infection, tuberculosis, and Trypanosoma cruzi infection) are latent in transplanted tissues. Transmission may also be due to active donor infection such as vire- mia or bacteremia that was undiscovered at the time of (Fig. 1A).3 Organ donors also may become infected with nosocomial organisms that are resistant to rou- tine surgical antimicrobial prophylaxis, and they may transmit these organisms (e.g., vancomycin- B resistant enterococcus and azole-resistant candida ) to recipients.4-6 Clusters of infections derived from deceased donors have been described, including transplan- tation-associated West Nile virus infection, lym- phocytic choriomeningitis virus infection, , virus (HIV) infection, and Chagas’ disease.3,7-10 In recent outbreaks of West Nile virus infection, lymphocytic choriomen- ingitis virus infection, and rabies, signs of infec- tious encephalitis in organs from deceased donors were masked by unrelated acute neurologic events and thus were not recognized. Figure 1. Effect of Donor-Derived Infection or Nonspecific signs such as altered mental status Injury on the Risk of Infection after Transplantation. or abnormal results of -function tests may be Panel A is a radiograph showing result- ing ICMfrom donor-derivedAUTHOR Fishman virusRET infection.AKE 1st the sole basis on which to investigate potential 2nd FeverREG and F pneumoniaFIGURE 1a&b developed of 5 in a -transplant donor-related infections. In the normal host, in- CASE 3rd recipient 3 TITLEdays after a technically successful Revisedtransplanta- fections due to West Nile virus or lymphocytic tion,EMail and the patient had abnormalLine results4-C on liver-func- Enon SIZE choriomeningitis virus are generally self-limited. tion tests. BloodARTIST :andmst sputumH/T containedH/T herpes simplex FILL Combo 16p6 However, in organ-transplant recipients with these virus. This virus was also detected in donor serum by means of a polymerase-chain-reactionAUTHOR, PLEASE NOTE: assay. Recipients infections, rapid progression, permanent neuro- Figure has been redrawn and type has been reset. logic damage, and are more common be- of the liver, , andPlease other check kidney carefully from. the same donor were symptomatic and were treated successfully with an- cause of the broad immunologic deficits that are tiviralJOB: therapy. 35725 Panel B is a computedISSUE: tomographic12-20-07 scan present after transplantation. showing a liver abscess at the site of an ischemic graft in- The screening of transplant donors for infec- jury. The patient had persistently and mildly abnormal tion is limited by the available technology and by liver-function tests (elevated alkaline phosphatase and to- the short period during which organs from de- tal bilirubin levels) after undergoing technically success- ful orthotopic with early graft isch- ceased donors can be used. At present, the routine emia. Three years later, fever and chills developed, and evaluation of donors for infectious disease gener- a heterogeneous 6-cm abscess (arrow) with intrahepatic ally relies on antibody detection with the use of biliary ductal dilatation was detected. Therapy included serologic tests for common infections (Fig. 2). percutaneous drainage and administration of antimicro- Since seroconversion may not occur during acute bial agents for organisms including vancomycin-resistant Enterococcus faecalis and Candida glabrata. infections and the sensitivity of these tests is not 100%, some active infections remain undetected. Some organs that contain unidentified pathogens curement organizations. Augmented screening is will inevitably be implanted. Improved donor recommended on a regional basis for endemic or screening will require the use of more sensitive epidemic infections such as West Nile virus infec- (e.g., molecular) and rapid assays by organ-pro- tion, Chagas’ disease, and .11

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Some documented infections, such as sepsis and HIV infection, preclude . Or- Donor Screening gans from donors with specified known infec- Epidemiologic history Serologic testing for VDRL, HIV, tions may be considered for specific recipients — CMV, EBV, HSV, VZV, HBV provided there is appropriate informed consent (HBsAg, anti-HBsAg), and HCV Microbiologic testing of — based on the urgency of the need for transplan- and urine Risk Assessment tation and the availability of effective antimicro- Chest Higher risk of infection Known infections (appropriate Induction therapy with lympho- bial . For example, some from do- therapy?) cyte depletion nors who were seropositive for Chagas’ disease Possible infections (e.g., encepha- Pulsed-dose litis, sepsis) Plasmapheresis have been used successfully with benznidazole Special serologic testing, nucleic High risk of rejection prophylaxis in regions where the disease is en- acid assays, or antigen detection Early graft rejection 12 based on epidemiologic factors Graft dysfunction demic. Similarly, although organs from donors and recent exposures (e.g., toxo- Active or latent infection in the infected with the B virus (HBV) and who plasma, West Nile virus, HIV, donor or recipient HCV) Technical complications had test results that were positive for antibodies Anastomotic leak against core antigen and negative for Bleeding antibodies against hepatitis B surface antigen were Wound infection or poor Recipient Screening healing Prolonged rejected in the past, they are currently used for Epidemiologic history Prolonged use of surgical, Vaccination history some recipients who have been vaccinated or who vascular, or urinary Serologic testing for VDRL, HIV, catheters were previously infected, provided there is treat- CMV, EBV, HSV, VZV, HBV Lower risk of infection (HbsAg, anti-HbsAg), and HCV ment with specific antiserum and anti-HBV anti- Immunologic tolerance Tuberculin skin test 13-18 Good HLA match viral agents. The use of organs infected with Microbiologic testing of blood Technically successful and urine the virus (HCV) remains controversial Good graft function Chest radiography Appropriate surgical prophylaxis and is generally reserved for HCV-infected re- Known infections Effective antiviral prophylaxis Past colonization: prophylaxis? cipients. Prophylaxis against pneumo- Active infection: appropriate cystis pneumonia Transplantation of organs from deceased do- therapy? Appropriate vaccination nors who had fever or viral syndromes is contro- Possible infections (e.g., encepha- litis, sepsis) versial, and the uncertainty highlights the need Special serologic testing, nucleic for improved microbiologic screening tools. In acid assays, or antigen detection based on epidemiologic factors cases in which the need for transplantation is rela- and recent exposures (e.g., tively less urgent, it is reasonable to avoid the use strongyloides, histoplasma, coccidioides, HBV or HCV of organs from donors with unexplained fever, ) rash, encephalitis, or untreated infectious syn- dromes. Figure 2. Assessment of the Risk of Infection at the Time Recipient-Derived Infections and Detection of Transplantation. Active infection in transplant recipients should be The risk of infection transmitted from the organ donor or activated in the RETAKE 1st recipient can beICM assessedAUTHOR: at theFishman time of transplantation. Donor and recipi- eradicated before transplantation, since immuno- 2nd ent screening REGare FbasedFIGURE: on the2 of epidemiologic 5 history and serologic testing. suppression will exacerbate the infectious process. The use of sensitive molecular and -based assays may enhance3rd the CASE Revised safety of while expanding the use of potentially in- Individualized epidemiologic histories can guide EMail Line 4-C SIZE preventive strategies.11 Common recipient-derived fected grafts. The transplantARTIST: recipient’sts H/T risk is H/Ta function of the technical Enon Combo 22p3 pathogens include Mycobacterium tuberculosis, certain outcome, epidemiologic factors, and the intensity of immunosuppression. VDRL denotes Venereal DiseaseAUTHOR, Research PLEASE Laboratory NOTE: test, HIV human im- parasites (e.g., Strongyloides stercoralis and T. cruzi), munodeficiency virus,Figure CMV has been cytomegalovirus, redrawn and type EBV has beenEpstein–Barr reset. virus, Please check carefully. (e.g., cytomegalovirus, EBV, herpes simplex HSV , VZV varicella–zoster virus, HBV , HBsAg hepatitis B surface antigen, anti-HBsAg antibodies against virus, varicella–zoster virus [which causes shin- JOB: 35725 ISSUE: 12-20-07 gles], HBV, HCV, and HIV), and endemic fungi hepatitis B surface antigen, and HCV . (e.g., Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides brasiliensis).19-29 Activities such as travel, raising pigeons (which is associated with Temporally distant S. stercoralis infection may neoformans infection), or marijuana use reemerge, often in the first year after transplan- (which is associated with infection with aspergil- tation, as a hyperinfestation syndrome consisting lus species) increase the risk of infection. Infec- of hemorrhagic enterocolitis, pneumonia, and tions that can be treated or controlled do not pre- gram-negative bacteremia or .24,25 Em- clude transplantation. pirical treatment with ivermectin before trans-

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plantation prevents such infection in strongyloi- Figure 3 (facing page). Dynamic Assessment of the Risk des-seropositive recipients. The importance of of Infection after Transplantation. donor-derived or recipient-derived exposures to The risk of infection is a function of the net state of im- endemic fungi such as H. capsulatum or tubercu- munodeficiency. The presence of specific, common in- losis is shown by the increased rate of activation fections can be detected by means of quantitative as- of these infections among transplant recipients; says measuring nucleic acids or derived from this rate is 50 times higher among transplant re- potential pathogens. Multiple simultaneous quantita- tive (multiplex) assays can be performed diagnostically cipients than it is among the general population, in a single sample with the use of polymerase chain re- notably in endemic regions.11 action. Each line represents a single patient’s sample The course of HCV infection after liver trans- (Panel A). The presence of specific infections can be plantation remains discouraging. Since effective assessed with the use of genomic arrays measuring the antiviral therapies are lacking, recipients are uni- up-regulation or down-regulation of host genes during infection (Panel B, courtesy of Shaf Keshavjee, M.D., formly reinfected by HCV, with outcomes deter- University of ). Lytic and latent epitopes are vi- mined by the viral strain, the presence or absence ral presented in either the lytic or latent phase of previous immunity, and the response to anti- of Epstein–Barr virus (EBV) infection. The transplant viral therapy.30-34 recipient’s cellular immune response to specific patho- Successful transplantation has been achieved gens such as EBV can be determined by measurements of cellular activation by pathogen-specific antigens in HIV-infected patients treated with highly ac- (Panel C, courtesy of Christian Brander, Massachusetts tive antiretroviral therapy.26-28 In such recipients, General Hospital). The factors contributing to the de- the toxic effects of drugs and interactions between gree of immunologic impairment and standard assays inhibitors and antiretroviral agents that assess the patient’s risk of infection will be sup- require careful monitoring. Liver-transplant re- plemented in the future by new quantitative measures of allograft- and pathogen-specific immune function cipients with HIV and HCV coinfection may have and the risk of infection (Panel D). RFU denotes rela- an accelerated course of recurrent HCV infection. tive fluorescence units, CMV cytomegalovirus, BK poly- omavirus type BK, HHV-6 , HHV- Nosocomial Infections and Antimicrobial Resistance 7 human herpesvirus 7, PBMCs peripheral-blood Patients waiting for transplantation may become mononuclear cells, SLE systemic lupus erythematosus, HCV hepatitis C virus, and HBV hepatitis B virus. colonized with nosocomial, antimicrobial-resistant organisms, including methicillin-resistant Staphy- lococcus aureus, vancomycin-resistant enterococcus, pressive therapies. Drug levels are used to guide -resistant candida species, Clostridium . This approach often results in difficile, and antimicrobial-resistant gram-negative toxic effects from drugs (e.g., renal injury from cal- bacteria or aspergillus species.35-43 After trans- cineurin inhibitors) and infection or graft rejec- plantation, these pathogens may cause pneumo- tion. These relatively crude measures of immu- nia or may infect hematomas, ascitic fluid, wounds, nosuppression may eventually be supplanted by and catheters. assays that allow individualization (minimization) of immunosuppression. Some nonspecific and Community Infections pathogen-specific measures of -mediated im- Exposures that are relatively benign in a normal mune function are available.44 Unique patterns host may lead to major infection after transplan- of gene and protein expression have been observed tation. Common microorganisms include those with specific infections and with graft rejection. noted above, pathogens in soil such as aspergillus In the future, new assays based on these patterns or nocardia species, C. neoformans in birds, and re- may guide the use of immunosuppression to pre- spiratory viruses with subsequent bacterial or fun- vent rejection and infection or to provide care for gal superinfection. patients with active infection (Fig. 3).

Net State of Immunosuppression PREVENTION OF INFECTION and Monitoring of Immune Function The net state of immunosuppression refers to all Antimicrobial prophylaxis has dramatically altered factors that contribute to the patient’s risk of in- the incidence and severity of post-transplantation fection (Fig. 3). The main determinants of risk are infections (Fig. 4). Three general preventive strat- the dose, duration, and sequence of immunosup- egies are used: vaccination, universal prophylaxis,

2604 n engl j med 357;25 www.nejm.org december 20, 2007 Medical Progress

A CMV BK

6 6 5 5 4 4 Area (RFU)

10 3 3

Log 2 2 15 20 25 30 35 40 45 15 20 25 30 35 40 45 Cycle No. Cycle No.

HHV-6 HHV-7

6 6 5 5 4 4 Area (RFU)

10 3 3

Log 2 2 15 20 25 30 35 40 45 15 20 25 30 35 40 45 Cycle No. Cycle No.

B C Lytic Epitopes Latent Epitopes

P=0.28 P=0.003 ≥1000 ≥1000 PBMCs)

800 800 6

0 600 600 400 400 200 200

100 100

0 0 Cases Controls Cases Controls EBV-Specific Cells (per 1

D

Net State of Immunodeficiency Standard Assays Advanced Assays Immunosuppressive therapy Serologic tests for seroconversion Multiplex microbiologic assays Previous therapies (e.g., chemotherapy, Microbiologic cultures and suscepti- Molecular antimicrobial-susceptibility testing antimicrobial agents) bility testing Nonspecific immunoassays for degree of im- Mucocutaneous-barrier integrity Quantitative viral-load assay and munosuppression (for catheters, drains) antigen tests Intracellular ATP , lymphopenia Histopathological tests and immuno- Biomarkers of rejection (cytokines) Underlying staining Proteomics (e.g., , SLE) Assays of pathogen-specific immunity Metabolic conditions (e.g., uremia, Cytotoxic lymphocytes malnutrition, diabetes, cirrhosis) Mixed lymphocyte cultures Viral infection (e.g., CMV, HCV, HBV) HLA-linked tetramers Intracellular cytokine staining Enzyme-linked immunospot assay Interferon-release assays Genomics (patterns of gene expression) in: Immunosuppression Infection Rejection Drug metabolism

RETAKE 1st ICM AUTHOR: Fishman 2nd REG F FIGURE: 3 of 5 3rd n englCASE j med 357;25 www.nejm.org decemberRevised 20, 2007 2605 EMail Line 4-C SIZE ARTIST: ts H/T H/T 33p9 Enon Combo AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

JOB: 35725 ISSUE: 12-20-07 T h e new england journal o f medicine

Nosocomial, technical Activation of latent infection Donor-Derived Community-acquired (donor or recipient) (relapsed, residual, opportunistic) Infection

Dynamic assessment of risk of infection Transplantation

Common Infections in Solid-Organ Transplant Recipients

Recipient-Derived <1 Month 1–6 Months >6 Months Infection Infection with antimicrobial- With PCP and antiviral (CMV,HBV) Community-acquired pneumonia, resistant species: prophylaxis: urinary tract infection MRSA Polyomavirus BK infection, nephropathy Infection with aspergillus, atypical VRE C. difficile colitis molds, mucor species Candida species (non-albicans) HCV infection Infection with nocardia, rhodo- Aspiration , coccus species Catheter infection Cryptococcus neoformans infection Late viral infections: Wound infection Mycobacterium tuberculosis infection CMV infection (colitis and Anastomotic leaks and Anastomotic complications retinitis) Clostridium difficile colitis Hepatitis (HBV, HCV) Without prophylaxis: HSV encephalitis Donor-derived infection Pneumocystis Community-acquired (SARS, (uncommon): Infection with herpesviruses (HSV, West Nile virus infection) HSV, LCMV, rhabdovirus VZV, CMV, EBV) JC polyomavirus infection (PML) (rabies), West Nile virus, HBV infection Skin cancer, lymphoma (PTLD) HIV,Trypanosoma cruzi Infection with listeria, nocardia, toxo- plasma, strongyloides, leishmania, Recipient-derived infection T. cruzi (colonization): Aspergillus, pseudomonas

Figure 4. Changing Timeline of Infection after Organ Transplantation. Infections occur in a generally predictable pattern after solid-organ transplantation. The development of infection is delayed by prophy- RETAKE 1st laxis and accelerated by intensified immunosuppression,ICM AUTHOR: drugFishman toxic effects that may cause leukopenia, or immunomodulatory viral in- 2nd fections such as infection with cytomegalovirusREG F(CMV),FIGURE: hepatitis4 of 5 C virus (HCV), or Epstein–Barr virus (EBV). At the time of transplanta- 3rd tion, a patient’s short-term and long-term riskCASE of infection can be stratified accordingRevised to donor and recipient screening, the technical outcome of surgery, and the intensity of immunosuppressionEMail requiredLine to prevent4-C graft rejection.SIZE Subsequently, an ongoing assessment of the risk of infection is used to adjust both prophylaxisARTIST: andts immunosuppressiveH/T H/T therapy. MRSA denotes methicillin-resistant Staphylo- Enon 39p6 coccus aureus, VRE vancomycin-resistant Enterococcus faecalis, HSV herpesCombo simplex virus, LCMV lymphocytic choriomeningitis virus, HIV human immunodeficiency virus, PCP Pneumocystis carinii AUTHOR,pneumonia, PLEASE HBV NOTE: hepatitis B virus, VZV varicella–zoster virus, SARS severe acute respiratory syndrome, PML progressive multifocalFigure has leukoencephalopathy, been redrawn and type has and been PTLD reset. post-transplantation lymphoproliferative disor- Please check carefully. der. Modified from Fishman and Rubin1 and Rubin et al.45

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and preemptive therapy.46 The need for immu- Promoting lifestyle changes after transplanta- nization against , , rubella, diph- tion may help limit exposures to some potential theria, pertussis, tetanus, HBV infection, - pathogens. Attention to hand washing should be , varicella, influenza, and pneumococcal observed after food preparation, gardening, and pneumonia should be evaluated before transplan- contact with feces or secretions. Transplant re- tation.47 Vaccination is generally less effective dur- cipients should avoid close contact with people ing immunosuppression.11 Pneumococcal vaccine who have respiratory illnesses, and they should is recommended every 3 to 5 years, and influenza avoid environments such as construction sites, vaccine is recommended annually. Other vaccines which have known pathogens. Dietary advice are appropriate for patients who travel to regions might include avoidance of well water and lake where certain illnesses are endemic. Live vaccines water (which may contain cryptosporidium or are generally contraindicated after transplanta- giardia species), undercooked meats, unwashed tion, since they may cause disseminated infection fruits and vegetables, and unpasteurized dairy in immunocompromised hosts. The immunologic products (which may contain Escherichia coli or Liste- protection provided by vaccines may be limited in ria monocytogenes). extent or duration.48,49 Routine surgical prophylaxis varies, depending

2606 n engl j med 357;25 www.nejm.org december 20, 2007 Medical Progress on the organ transplanted and local epidemiologic trast, with preemptive therapy, sensitive quantita- factors. For liver transplantation, antimicrobial tive assays (e.g., molecular assays and antigen de- agents that provide coverage for skin flora, bili- tection) are used to monitor patients at predefined ary enterococcus species, anaerobes, and Entero- intervals in order to detect infection before symp- bacteriaceae are routinely prescribed. For toms arise. Depending on the potential pathogen transplantation, prophylaxis is aimed at gram- and institutional protocols, a positive assay trig- negative bacteria, molds, and geographic fungi gers the initiation of antimicrobial therapy, a re- (e.g., histoplasma). Prophylaxis may be adjusted duction in the intensity of immunosuppression, according to known colonization patterns with intensified monitoring, or all of these steps. Pre- pseudomonas, methicillin-resistant S. aureus, van- emptive therapy incurs extra costs for monitoring comycin-resistant enterococcus, or fungi. and coordination of outpatient care, but it avoids Antifungal prophylaxis is based on both risk the costs and toxic effects of prophylactic anti- and epidemiologic factors. Most invasive fungal viral therapy. infections in transplant recipients are due to non- The crude risk of specific infections has tradi- albicans candida and aspergillus species. The tionally been defined by means of serologic test- greatest risks associated with early fungal infec- ing; the risk is lower in a seropositive host or tions include aspergillus at the tracheal anasto- higher in a seronegative recipient of an organ from mosis after and candida a seropositive donor. A variety of newer techniques species after pancreas or liver transplantation. In- (e.g., HLA-linked tetramer binding and intracel- vasive fungal infections are most common in liver lular cytokine staining) measure pathogen-specific recipients requiring admission to the intensive care immunity and provide insight into the risk of spe- unit, surgical re-exploration or retransplantation, cific infections and the ability of the host to clear or transfusion of large amounts of blood prod- invasive disease (Fig. 3).59 ucts and in liver recipients with metabolic dys- function (involving the liver allograft, kidney, or CHANGING THE pattern diabetes), respiratory failure, cytomegalovirus in- OF INFECTION fection, or HCV infection. The risk is increased after broad-spectrum antimicrobial therapy.50-56 Early in the evolution of solid-organ transplan- Prophylaxis should be considered in such high- tation, there was a limited number of available risk hosts. immunosuppressive agents, and antirejection pro- Most transplantation centers use trimetho­ tocols (i.e., use of corticosteroids, calcineurin prim–sulfamethoxazole prophylaxis for as little as inhibitors, and ) were relatively stan- 3 months or for as long as a lifetime to prevent dardized. As a result, the timeline for the develop- as well as infections ment of common post-transplantation infections with , Isospora belli, Cyclospora cay- was relatively predictable.1,45 Changes in immu- etanensis, many nocardia and listeria species, and nosuppressive regimens, routine prophylaxis, and common urinary, respiratory, and gastrointestinal improved graft survival have altered the original pathogens. Low-dose trimethoprim–sulfamethox- pattern (Fig. 4). -sparing regimens azole is well tolerated and should be used unless and antipneumocystis prophylaxis have made there is evidence that the patient has an or pneumocystis pneumonia less common. Herpes- interstitial nephritis. Alternative agents for pro- virus infections are uncommon while patients are phylaxis against pneumocystis include dapsone, receiving antiviral prophylaxis. Newer immuno- atovaquone, and pentamidine, but they are less suppressive approaches, including the use of si- effective than trimethoprim–sulfamethoxazole rolimus, mycophenylate mofetil, T-cell and B-cell and lack the breadth of protection.57 depletion, and costimulatory blockade, have largely The prevention of post-transplantation cyto- replaced high-dose corticosteroids and azathio- megalovirus and other herpesvirus infections and prine. the availability of oral antiviral agents have revo- With changes in typical immunosuppression, lutionized post-transplantation care.58 Two pre- new patterns of infection have emerged. Sirolimus- ventive strategies have emerged. With universal based regimens have been associated with idio- prophylaxis, antimicrobial therapy is provided to syncratic noninfectious pneumonitis, which is all at-risk patients for a defined period. In con- easily confused with pneumocystis pneumonia or

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.60 T-lymphocyte–depleting anti- in the future, multiplex quantitative assays will be bodies commonly used for initial or induction used to monitor acute infections (Fig. 3). therapy are associated with increased viral acti- vation — notably, activation of cytomegalovirus, late post-transplantation period EBV, and HIV.28,61,62 Cellular depletion after in- The risk of infection diminishes 6 months after duction therapy often persists beyond the period transplantation, since immunosuppressive thera- of antimicrobial prophylaxis, resulting in late in- py is usually tapered in recipients who have satis- fections with viruses such as cytomegalovirus and factory allograft function. However, transplant JC polyomavirus as well as fungal infections and recipients have a persistently increased risk of in- malignant conditions after transplantation. Infec- fection due to community-acquired pathogens (Fig. tions that occur after the usual period or that are 4). In some patients, chronic viral infections may unusually severe suggest excessive immunosup- cause allograft injury (e.g., cirrhosis from HCV in- pression or exposure. The timeline for a given fection in liver-transplant recipients, bronchiolitis patient is reset with each episode of rejection or obliterans in lung-transplant recipients, accelerated intensification of immunosuppression (e.g., with vasculopathy in heart-transplant recipients with bolus corticosteroids), with an increased risk of cytomegalovirus infection) or a malignant condi- opportunistic infections. tion such as post-transplantation lymphoprolif- erative disorder (PTLD) or skin or anogenital can- early post-transplantation period cers (Fig. 1). Recurrent infection may develop in Opportunistic infections are generally absent dur- some patients despite minimization of their im- ing the first month after transplantation, since the munosuppression. These patients are at increased full effect of immunosuppression is not yet pres- risk for with listeria or ent. Infections such as viremia and candidemia in nocardia species, invasive fungal pathogens such this period are generally donor-derived or recipi- as zygomycetes and dematiaceous molds, and un- ent-derived, or they are associated with technical usual organisms (e.g., rhodococcus species). Min- complications of surgery (Fig. 1B). Therapy must imal signs of infection merit careful evaluation be guided by antimicrobial-susceptibility data, in such high-risk patients; they may benefit from making microbiologic analysis of aspirates or bi- lifetime trimethoprim–sulfamethoxazole or anti- opsy specimens essential. C. difficile colitis is com- fungal prophylaxis. Such long-term prophylaxis mon in this setting. Early graft injuries (e.g., ische­ carries some risk of the development of microbial mia of bile ducts or pulmonary reperfusion injury) resistance to the prophylactic agents and possible may later become foci for liver or lung abscesses future drug interactions. (Fig. 1B). Unexplained early signs of infection, such as hepatitis, pneumonitis, encephalitis, rash, and Common Infections leukopenia, may be donor-derived. in Transplantation

intermediate post-transplantation period Early and specific microbiologic diagnosis is es- Viral pathogens and allograft rejection are respon- sential in the immunocompromised host, often sible for the majority of febrile episodes that oc- necessitating invasive diagnostic techniques. Re- cur during the period from 1 to 6 months after duction in the intensity of immunosuppression may transplantation. Trimethoprim–sulfamethoxazole be useful until the acute process is controlled, al- prophylaxis generally prevents most urinary tract though this approach risks allograft rejection. Re- infections and opportunistic infections such as versal of immune deficits such as neutropenia or pneumocystis pneumonia, L. monocytogenes infec- hypogammaglobulinemia may be achieved by the tion, T. gondii infection, and infection with sulfa- administration of colony-stimulating factors or in- susceptible nocardia species. Infection due to en- travenous immune globulin. Viral coinfection must demic fungi, aspergillus, cryptococcus, T. cruzi, or be recognized and treated. strongyloides may occur. Herpesvirus infections are uncommon with antiviral prophylaxis. How- Cytomegalovirus infection ever, other viral pathogens, including polyomavi- Cytomegalovirus infection may cause both inva- rus BK, adenovirus, and recurrent HCV, have sive disease, or “direct effects,” and a variety of emerged. Given the array of potential pathogens, secondary immune phenomena (Fig. 5) in trans-

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Antilymphocyte globulin, fever, Latent CMV infection TNF-α, infection, high-dose immunosuppression

Active CMV infection (viremia and tissue infection)

Cellular effects: CMV disease MHC, cytokine expression “Direct effects” “Indirect effects”

CMV syndrome End-organ disease Allograft Allograft EBV-associated Opportunistic (Fever, weakness, (Nephritis, hepatitis, injury rejection PTLD infection myalgia, arthralgia, carditis, colitis, myelosuppression) pneumonitis, retinitis, encepha- litis) Atheroclerosis, bronchiolitis obliterans, vanishing bile duct syndome

Figure 5. Cytomegalovirus Infection. Cytomegalovirus (CMV) causes both invasive disease (“direct effects”) and immunologic phenomena (“indirect effects”), including graft rejection and a predisposition to opportunistic infections. CMV may be activated by febrile illness (through the release of tumor RETAKE 1st ICM AUTHOR: Fishman necrosis factor α [TNF-α]), by depletion of antilymphocyte antibodies, or during treatment for2nd graft rejection. MHC denotes major histo- REG F FIGURE: 5 of 5 compatibility complex, EBV Epstein–Barr virus, and PTLD post-transplantation lymphoproliferative3rd disorder. CASE Revised EMail Line 4-C SIZE ARTIST: ts 1,63,64 H/T H/T plant recipients. Invasive disease generallyEnon oc- terminingCombo a patient’s risk39p6 of infection, but they are curs during the first year after completion of pro- AUTHOR,generally PLEASE of little NOTE: use in the diagnosis of acute in- Figure has been redrawn and type has been reset. phylaxis and is manifested most often as fever and fections.Please check Seropositivity carefully. is also associated with the neutropenia; some patients have lymphadenopa- presence of cellular immunity.65 Primary infection, thy, hepatitis, , pneumonitis,JOB: 35725 the most severe formISSUE: of 12-20-07disease, occurs when se- gastrointestinal invasion (with diffuse colitis, gas- ronegative recipients who have not previously re- tritis, ulcers, and bleeding), , chorio- ceived immunologic therapy receive allografts from retinitis (which is often late), or meningoenceph- latently infected, seropositive donors (i.e., D+/R– alitis (which is uncommon). Cytomegalovirus combinations). Without antiviral prophylaxis, most infection is also associated with an overall in- newly infected patients have vire- crease in the risk of additional infections, includ- mia, although invasive disease develops in a sub- ing infections with other viruses and EBV-associ- group of patients. Seroconversion in seronegative ated PTLD. In addition, cytomegalovirus infection transplant recipients who have received allografts may contribute to vasculopathy in heart-allograft from seropositive donors generally occurs during recipients and to the bronchiolitis obliterans syn- the first year after transplantation; however, 25% drome in lung-allograft recipients. of recipients do not undergo seroconversion and may benefit from prolonged prophylaxis.66 Epidemiology Primary infection, reactivation, or viral superinfec- Prevention tion with cytomegalovirus may develop in trans- Both universal antiviral prophylaxis and preemp- plant recipients. Serologic assays are useful in de- tive antiviral therapy reduce the risk of invasive

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cytomegalovirus infection.67-69 Universal antiviral tance may present as slowly responsive or relaps- prophylaxis also helps to prevent other viral infec- ing infection, most commonly in patients who tions such as herpes simplex virus, varicella–zos- were seronegative for cytomegalovirus at the time ter virus, EBV, and human herpesvirus 6 (HHV-6) of transplantation and received allografts from and human herpesvirus 7 (HHV-7) infections. Uni- seropositive donors, in patients who receive in- versal antiviral prophylaxis also reduces the risk adequate or prolonged doses of oral ganciclovir or of fungal infections such as pneumocystis, candi- , especially during active infection, da, and aspergillus, complications of viral infec- or in patients who undergo intensified immuno- tions such as HHV-6, HHV-7, accelerated HCV and suppression. Recipients of lung transplants are PTLD, and bacterial infections (Fig. 4).54,70-73 In also at relatively high risk for resistance to gan- addition, prevention of cytomegalovirus infection ciclovir. Ganciclovir resistance has been ob- may reduce episodes of both early and late acute served with both universal and preemptive ap- rejection in renal-transplant recipients, cardiac proaches.82-84 vasculopathy in heart-transplant recipients, and the bronchiolitis obliterans syndrome in lung- Diagnosis and Therapy transplant recipients (Fig. 5).74-79 The relationship Quantitative diagnostic assays for cytomegalovi- between acute rejection and cytomegalovirus dis- rus are essential for management of infection. ease has not been shown in all studies.80 These include molecular assays (polymerase-chain- Although optimal regimens remain undefined, reaction [PCR] and other amplification assays) and most centers provide anticytomegalovirus pro- antigen-detection (pp65 antigenemia) assays. In phylaxis for the first 3 to 6 months after trans- patients with neurologic manifestations of cyto- plantation, using valacyclovir, high-dose acyclovir, megalovirus infection (including chorioretinitis) ganciclovir, valganciclovir, or, less commonly, cy- and gastrointestinal disease (colitis and gastritis, tomegalovirus hyperimmune globulins.1,81 Sever- often with ulceration), blood-based cytomegalo- al situations require special consideration. First, virus assays may be negative. Thus, invasive pro- the use of induction therapy with depleting anti- cedures such as colonoscopy with or lum- lymphocyte antibodies for seropositive donors or bar puncture may be necessary. Invasive disease seropositive recipients increases the risk of cyto- and the cytomegalovirus syndrome (which is man- megalovirus reactivation and generally merits ex- ifested as fever and leukopenia) warrant therapy, tended prophylaxis followed by monitoring for generally with intravenous ganciclovir. Results of active infection. Second, although recipients of studies of oral valganciclovir therapy for cytomeg- heart and lung transplants who are seropositive or alovirus disease are encouraging.85,86 Intravenous who receive transplants from seropositive donors ganciclovir is currently preferred for the initiation generally receive prophylaxis for at least 6 to 12 of therapy for gastrointestinal disease. Documen- months, some may benefit from longer courses tation of cure in patients with gastrointestinal cy- of antiviral prophylaxis if they lack evidence of tomegalovirus infection includes negative results protective immunity (i.e., if they have not under- of microbiologic assays and healing of ulcers and gone seroconversion), if they have persistent vi- colitis on endoscopic evaluation. Relapse, which ral secretion (e.g., in sputum), or if they require is common with inadequate therapy, carries the a greater intensity of sustained immunosuppres- risk of the emergence of resistance to antiviral sion. However, patients receiving longer courses agents. of ganciclovir or valganciclovir may incur marrow suppression from these agents. Some patients Epstein–Barr Virus and Post-Transplantation treated for active cytomegalovirus infection may Lymphoproliferative Disorder have a relapse without an additional period of pro- PTLD, a heterogeneous group of lymphoprolifera- phylaxis after treatment. tive disorders, occurs in 3 to 10% of adults who Ganciclovir resistance in patients with cyto- are solid-organ transplant recipients; it is associ- megalovirus infection is uncommon, but when ated with a reported mortality of 40 to 60%.87-89 present, it is most often due to mutations in the PTLD accounts for more than half of post-trans- cytomegalovirus UL97 gene (a viral protein kinase plantation malignant conditions in pediatric solid- that phosphorylates the drug) or the UL54 gene organ–transplant recipients. It varies from a (cytomegalovirus DNA polymerase). Such resis- benign polyclonal, B-cell, infectious mononucle-

2610 n engl j med 357;25 www.nejm.org december 20, 2007 Medical Progress osis-like syndrome to malignant, monoclonal lym- Table 1. Clinical Presentations of Post-Transplantation Lymphoproliferative 90-92 phoma. Risk factors for PTLD include primary Disorder Associated with Epstein–Barr Virus. EBV infection after transplantation in seronega- tive recipients of allografts from seropositive do- Unexplained fever (fever of unknown origin) nors, allograft rejection, exposure to antilympho- Mononucleosis-like syndrome (fever, malaise, pharyngitis, tonsillitis) cyte antiserum, and cytomegalovirus coinfection. Gastrointestinal bleeding, obstruction, or perforation PTLD occurring in the first year after transplan- Abdominal-mass lesions tation is usually CD20+ and B cell in origin. In Infiltrative disease of the allograft contrast, later disease may be EBV-negative and Hepatocellular or pancreatic dysfunction , natural killer cell, or null cell in origin, generally with a worse prognosis. Central nervous system disease The role of EBV in non–B-cell PTLD is less clear. The clinical presentation of EBV-associated viral DNA synthesis that has considerable neph- PTLD varies (Table 1). PTLD is generally extra- rotoxicity; , an immunosuppressive nodal, often with mass lesions in proximity to the agent with antiviral properties against BK virus transplanted organ. Both B-cell and T-cell PTLD and cytomegalovirus; and intravenous immune may infiltrate allografts and may be confused with globulin. None of these agents have been shown allograft rejection or other viral processes. Oc- to have efficacy in the treatment of polyomaviruses casionally, patients with PTLD have evidence of or have been subjected to rigorous controlled tri- remitting–relapsing EBV infection, which reflects als. In patients with renal failure due to polyoma- an interplay between antiviral immunity and im- virus-associated nephropathy, successful retrans- munosuppression. plantation has been achieved after reversal of Quantitative EBV viral-load testing, flow cytom- immunosuppression for a sufficient time to allow etry, analysis of immunoglobulin gene rearrange- the emergence of antiviral immunity.98,99 ments, and histologic analysis with staining for EBV-derived RNA are helpful in guiding the diag- Central Nervous System Infection nosis and management of PTLD.93,94 In the poly- Central nervous system infection in transplant clonal form, particularly in children, a reduction recipients is a medical emergency. The broad spec- in immunosuppression may lead to regression of trum of causative organisms includes listeria, her- the PTLD but poses the risk of allograft rejection. pes simplex virus, JC virus, and C. neoformans. Em- The progression of disease requires alternative ap- pirical therapy must be initiated while the results proaches that may include the administration of of imaging studies (preferably magnetic resonance chemotherapy, irradiation (for central nervous sys- imaging), lumbar puncture (including studies such tem disease), and treatment with anti-CD20 an- as PCR for detection of herpes simplex virus and tibodies. Adoptive immunotherapy (T-cell trans- cryptococcal antigen), blood cultures, and other fer) is under investigation as a treatment strategy cultures are pending. Included in the differential for PTLD. Further data are needed to define a pos- diagnosis are noninfectious causes such as toxic sible protective role of sirolimus against PTLD.93 effects of calcineurin inhibitors and lymphoma.

Polyomaviruses BK and JC Pneumonitis and Pneumocystis Infection Polyomaviruses have been identified in transplant Pneumocystis pneumonia remains common in the recipients in association with nephropathy (e.g., absence of specific prophylaxis.56,100 Pneumocys- polyomavirus BK–associated nephropathy) and tis pneumonia should be considered in patients in ureteral obstruction, and the JC virus has been whom marked hypoxemia, dyspnea, and cough de- associated with progressive multifocal leukoen- velop in spite of a paucity of physical or radiologic cephalopathy.95-99 No effective antiviral therapy findings. No radiographic patterns are pathogno- exists for polyomaviruses. Detection of BK virus monic in the immunocompromised host. Com- nucleic acids in blood and urine has been useful puted tomographic imaging is useful to define for assessing responses to therapy in patients with the extent of disease and to direct invasive tech- polyomavirus-associated nephropathy. Therapy re- niques for microbiologic sampling. Noninfectious quires a reduction in immunosuppression. Experi- processes may contribute to the pathogenesis of mental therapies include , an inhibitor of pneumonitis; these processses include the toxic

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effects of sirolimus, which may be obscured by sponsiveness to latent organisms in that organ. coinfection.60 Techniques currently under development, such as more sensitive microbiologic assays, immuno- Conclusions assays, and genomic and proteomic markers, may provide the potential for individualized immu- The study of infectious diseases associated with nosuppression and prophylactic strategies (Fig. transplantation focuses on the prevention of infec- 3).103,104 Such assays may ultimately permit a tion in transplant recipients. The interaction of in- more dynamic assessment of the immune status fection and immunosuppression is the central con- of transplant recipients over time, allowing titra- cern. The induction of immunologic tolerance so tion of immunosuppression and reducing that exogenous immunosuppression is avoided in from infection and malignant conditions.105 transplant recipients, might, if successful, reduce Dr. Fishman reports serving as a consultant to Gilead Phar- the risk of infection after transplantation. Howev- maceuticals, Merck, , Biogen Idec, Hoffmann– La Roche, ViroPharma, Pfizer, and Schering-Ploughbeing; be- er, two caveats would remain. First, exposures to ing a member of the scientific advisory board and receiving infections subsequent to the development of toler- consulting fees from Primera; receiving grant support from As- ance might abrogate tolerance and induce allograft tellas Pharma; and holding two international patents (US 101,102 5442050, awarded in 1995, and US6190861, awarded in 1997) rejection. Second, the induction of tolerance owned by Massachusetts General Hospital. No other potential to an allograft might induce immunologic unre- conflict of interest relevant to this article was reported.

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